Obesity is a major public health concern because of its increasing prevalence and associated health risks. Moreover, obesity may affect a person's quality of life through limited mobility and decreased physical endurance as well as through social, academic and job discrimination.
Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and serves as a measure of the risk of certain diseases. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, and obesity is typically defined as a BMI of 30 kg/m2 or higher. See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, D.C.: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).
Recent studies have found that obesity and its associated health risks are not limited to adults, but also affect children and adolescents to a startling degree. According to the Center for Disease Control, the percentage of children and adolescents who are defined as overweight has more than doubled since the early 1970s, and about 15 percent of children and adolescents are now overweight. Risk factors for heart disease, such as high cholesterol and high blood pressure, occur with increased frequency in overweight children and adolescents compared with normal-weight subjects of similar age. Also, type 2 diabetes, previously considered an adult disease, has increased dramatically in children and adolescents. Overweight conditions and obesity are closely linked to type 2 diabetes. It has recently been estimated that overweight adolescents have a 70% chance of becoming overweight or obese adults. The probability increases to about 80% if at least one parent is overweight or obese. The most immediate consequence of being overweight as perceived by children themselves is social discrimination.
There are possible adverse health consequences of being overweight or obese as such individuals are at increased risk for ailments (co-morbidities) such as hypertension, dyslipidemia, type 2 (non-insulin dependent) diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, stroke, gallstones, cholescystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, gall bladder disease, certain forms of cancer (e.g., endometrial, breast, prostate, and colon) and psychological disorders (such as depression, eating disorders, distorted body image and low self esteem). The negative health consequences of obesity make it the second leading cause of preventable death in the United States and impart a significant economic and psychosocial effect on society. See, McGinnis M, Foege W H., “Actual Causes of Death in the United States,” JAMA, 270, 2207-12 (1993).
Obesity is now recognized as a chronic disease that requires treatment to reduce its associated health risks. Although weight loss is an important treatment outcome, one of the main goals of obesity management is to improve cardiovascular and metabolic values to reduce obesity-related morbidity and mortality. It has been shown that 5-10% loss of body weight can substantially improve metabolic values, such as blood glucose, blood pressure, and lipid concentrations. Hence, it is believed that a 5-10% intentional reduction in body weight may reduce morbidity and mortality.
Currently available prescription drugs for managing obesity generally reduce weight by primarily inducing satiety or decreasing dietary fat absorption. Satiety is achieved by increasing synaptic levels of norepinephrine, serotonin, or both. For example. stimulation of serotonin receptor subtypes 1B, 1D, and 2C and 1- and 2-adrenergic receptors decreases food intake by regulating satiety. See, Bray G A, “The New Era of Drug Treatment. Pharmacologic Treatment of Obesity: Symposium Overview,” Obes Res., 3(suppl 4), 415s-7s (1995). Adrenergic agents (e.g., diethylpropion, benzphetamine, phendimetrazine, mazindol, and phentermine) act by modulating central norepinephrine and dopamine receptors through the promotion of catecholamine release. Older adrenergic weight-loss drugs (e.g., amphetamine, methamphetamine, and phenmetrazine), which strongly engage in dopamine pathways, are no longer recommended because of the risk of their abuse. Fenfluramine and dexfenfluramine, both serotonergic agents used to regulate appetite, are no longer available for use.
Cholecystokinin (CCK) is a brain-gut peptide that acts as a gastrointestinal hormone, neurotransmitter and neuromodulator in the central and the peripheral nervous systems. Cholecystokinin is a peptide that exists in multiple active forms of varying lengths (e.g. CCK-58; CCK-39; CCK-33; CCK-8; and CCK-4), with different forms predominating in different species. Cholecystokinin-58 is the major molecular form in man, dog and cat but not in pig, cattle or rat intestine. See, e.g., G. A. Eberlien, V. E. Eysselein and H. Goebell, 1988, Peptides 9, pp. 993-998. CCK's peripheral effects, where the O-sulfated octapeptide CCK-8S is believed to be the predominate form, are centered on its role as a gastrointestinal satiety factor.
It has been shown that CCK is released from mucosal I-cells of the duodenum and jejunum in response to a meal, particularly in response to fat or protein in the meal. Once released, CCK initiates a number of responses coordinated to promote digestion and regulate food intake, including mediating bile emptying from the gall bladder, regulating the release of digestive enzymes from the pancreas, controlling gastric emptying by regulation of the pyloric sphincter, as well as neuronal signaling to the CNS (central nervous system) via vagal afferent neurons.
Within the CNS, CCK has been found in numerous anatomical locations, including the cerebral cortex, hippocampus, septum, amygdala, olfactory bulb, hypothalamus, thalamus, parabrachial nucleus, raphe nucleus, substantia nigra, ventral mesencephalon, nucleus tractus solatarius, ventral medulla, and spinal cord. See, e.g., T. Hokfelt et al., 1988, J. Chem. Neuroanat. 1, pp. 11-52; J. J. Vanderhaeghen, J. C. Signeu and W. Gepts, 1975, Nature 257, pp. 604-605; and J-J. Vanderhaegen and S. N. Schiffmann (1992) pp. 38-56, Eds. C. T. Dourish, S. J. Cooper, S. D. Iversen and L. L. Iversen, Oxford University Press, Oxford.
Neuronal CCK is believed to mediate a number of events within the CNS, including modulating dopaminergic neurotransmission and anxiogenic effects, as well as affecting cognition and nociception. See, e.g., J. N. Crawley and R. L. Corwin, 1994, Peptides, 15:731-755; N. S. Baber, C. T. Dourish, and D. R. Hill, Pain (1989), 39(3), 307-28; and P. De Tullio, J. Delarge and B. Pirotte, Expert Opinion on Investigational Drugs (2000), 9(1), 129-146.
Cholecystokinin has been shown to mediate its diverse hormonal and neuromodulatory functions through two receptor subtypes: the CCK-A (CCK1) and CCK-B (CCK2) subtypes (see, e.g., G. N. Woodruff and J. Hughes, Annu. Rev. Pharmacol. Toxicol. (1991), 31: 469-501), both of which have been sequenced and cloned from rats (see, e.g., S. A. Wank et al. (1992) Proc. Natl, Acad. Sci. USA, 89, 8691-8695) and humans (see, e.g., J. R. Pisegna et al., 1992, Biochem. Biophys. Res. Commun. 189, pp. 296-303).
Both CCK-A and CCK-B receptor subtypes belong to the seven transmembrane G-protein-coupled superfamily of receptors. The nucleotide sequences of the peripheral CCK-A receptor and central CCK-A receptor are identical in humans; likewise, the human CCK-B receptor and gastrin receptor have been found to be identical. See, e.g., S. A. Wank et al., (1994), NY Acad. Sci. 713, pp. 49-66.
The CCK-A receptor is located predominately in the periphery, including pancreatic acinar cells, pyloric sphincter, gall bladder, and vagal afferents, where it mediates pancreatic exocrine secretion, gastric emptying and gall bladder contraction, and transmits post-prandial satiety signals to the CNS. In addition, the CCK-A receptor is found in discrete regions within the CNS, including the nucleus tractus solatarius, area postrema, and the dorsal medial hypothalamus. The CCK-B receptor is located predominately in the CNS, and is less predominant in the periphery.
A number of studies suggest that CCK mediates its satiety effect through the CCK-A receptor, which relays the postprandial satiety signal via the vagal afferents to the CNS. See, e.g., G. P. Smith et al., Science 213 (1981) pp. 1036-1037; and J. N. Crawley et al., J. Pharmacol. Exp. Ther., 257 (1991) pp. 1076-1080. For example, it has been reported that CCK and CCK agonists can decrease food intake in animals, including rats (see, e.g., J. Gibbs, R. C. Young and G. P. Smith, 1973, J. Comp. Physiol. Psychol. 84:488-95), dogs and primates (including man) (see, e.g., B. A, Himick and R. E. Peter, 1994, Am. J. Physiol. 267:R841-R851; Y. Hirosue et al., 1993, Am. J. Physiol. 265:R481-R486; and K. E. Asin et al., 1992, Pharmacol. Biochem. Behav. 42:699-704), and that this anorectic effect is mediated via the CCK-A receptor located on vagal afferent fibers (see, e.g., C. T. Dourish, 1992, In Multiple cholecystokinin receptors in the CNS, C. T. Dourish, S. J. Cooper, S. D. Iversen and L. L. Iversen, editors, Oxford University Press, New York, N.Y., pp. 234-253; G. P. Smith and J. Gibbs, 1992, In Multiple cholecystokinin receptors in the CNS, C. T. Dourish, S. J. Cooper, S. D. Iversen and L. L. Iversen, editors, Oxford University Press, New York, N.Y., pp. 166-182; J. N. Crawley and R. L. Corwin, 1994, Peptides, 15.731-755, and G. P. Smith et al., 1981, Science 213, pp. 1036-1037).
Other lines of evidence supporting the involvement of the CCK-A receptor in regulating food intake include the finding that OLETF rats (which lack the CCK-A receptor) are insensitive to the anorexigenic action of CCK. Also, it has been reported that CCK-A selective antagonists, but not CCK-B antagonists, block the anorectic actions of CCK and CCK analogs and increase feeding in animals (see, e.g., G. Hewson et al., 1988, Br. J. Pharmacol. 93:79-84; R. D. Reidelberger and M. F. O'Rourke, 1989, Am. J. Physiol. 257: R1512-R1518; T. H. Moran et al., 1993, Am. J. Physiol. 265:R620-R624; and M. Covasa and R. C. Ritter, Peptides (New York, N.Y., US) (2001), 22(8), 1339-1348), including humans (see, e.g., O. M. Wolkowitz et al., 1990, Biol. Psychiatry, 28:169-173.
Finally, it has been reported that infusion of CCK or selective CCK-A agonists reduces meal size and caloric intake in animals, including humans (see, e.g., L. Degen et al., Peptides (New York, N.Y.) (2001), 22(8), 1265-1269, H. R. Kissileff et al., Am J Clin Nutr 34 (1981), pp. 154-160; A. Ballinger et al., Clin Sci 89 (1995), 375-381; and R. J. Lieverse et al., Gastroenterology 106 (1994), 1451-1454.
The development of non-peptidic CCK-A agonists has been reported in the literature. For example, Sanofi has reported in U.S. Pat. No. 5,798,353 that certain 3-acylamino-5-(polysubstituted phenyl)-1,4-benzodiazepin-2-ones act as CCK-A agonists. Certain 1,5-benzodiazepinones have been reported to be CCK-A agonists having anorectic activity in rodents (see, e.g., E. E. Sugg et al., (1998) Pharmaceutical Biotechnology 11 (Integration of Pharmaceutical Discovery and Development): 507-524). R. G. Sherrill et al., in Bioorganic & Medicinal Chemistry Letters (2001), 11(9), 1145-1148 disclose certain 1,4-benzodiazepines as being peripheral CCK-A receptor agonists with anorectic activity in rat feeding models. A series of 3-(IH-indazol-3-ylmethyl)-1,5-benzodiazepines is discussed by B. R. Henke et al. in J. Med. Chem. (1997), 40(17), 2706-2725 and J. Med. Chem. (1996), 39(14), 2655-2658 as being orally active CCK-A agonists.
Although investigations are ongoing, there still exists a need for a more effective and safe therapeutic treatment for reducing or preventing weight-gain.